N-substituted maleimide compounds



United States Patent Ofiice 3,337,583 Patented Aug. 22, 1967 3,337,583N-SUBSTITUTED MALEIMIDE COMPUUNDS Frances E. Knock, Glenview, Ill,assignor to E. R. Squibb & Sons, Inc, New York, N.Y., a corporation ofDelaware N Drawing. Filed Jan. 6, 1967, Ser. No. 607,632 4 Claims. (Cl.260-326.3)

ABSTRACT OF THE DISCLUSURE This invention relates to maleimidecompounds. More particularly, the invention relates to antibacterialcompounds of the formula R lower alkylene-N wherein R is hydrogen orlower alkyl, and R is lower alkoxy, carboxy and -NH-lower alkanoyl.

This application is a continuation-in-part of application Ser. No.395,910, filed Sept. 11, 1964, now abandoned.

In the new compounds of Formula I, the lower alkyl groups includestraight and branched chain hydrocarbon groups such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, t-butyl, amyl and the like. Thelower alkylene group is a divalent hydrocarbon chain of the samecharacter. The lower alkoxy groups are ether groups containing the samekind of alkyl group linked to the oxygen. The lower alkanoyl group isthe acyl radical of straight and branched chain lower fatty acids withtwo to seven carbon atoms in the acyl group, e.g., acetyl, propionylbutynyl, isobutyryl and the like.

The new compounds of this invention are produced by reacting theappropriately substituted alkylamine, e.g., an amine of the formula (II)R -lower alkylene-NI-ll with maleic anhydride or R-substituted maleicanhydride, and the maleamic acid which is the product of this reactionis cyclized for example, with acetic anhydride and sodium acetate at anelevated temperature in the range of about 70 to 100 C. Certain of theseproducts, particularly those with carboxy groups, form salts with alkalimetals and alkaline earth metals and organic bases.

The compounds of this invention are useful as antibacterial agents,e.g., to combat organisms such as Staphylococcus aureus, Proteusvulgarz's, Escherz'schia coll, Salmonella schottmuelleri andMycobacterium tuberculosis. They may be administered orally orparenterally in daily dosages of about to 120 mg. in conventional forms.The compound itself or a physiologically acceptable basic salt thereofis combined with a conventional pharmaceutical carrier, includingexcipient, lubricant, buifer, etc., according to accepted pharmaceuticalpractice. In this manner, tablets, capsules, elixirs, injectables andthe like for oral or parenteral use are provided. Disinfectant solutionsmay be prepared in conventional vehicles.

The following examples are illustrative of the invention. Temperaturesare expressed on the centigrade scale.

Example 1 To 9.8 gm. of maleic anhydride in 100 ml. of glacial aceticacid are added dropwise a solution of 10.2 gm.

of Z-aminoethylacetamide [JACS 63, 853 (1941)] in 50 ml. ofdimethylformamide with stirring in an ice bath. The mixture is stirredfor one hour at room temperature. The N-(Z-acetamidoethyl)maleamic acidformed is then precipitated from one liter of ether.

To 17 gm. of N-(Z-acetamidoethyl)maleamic acid are added 200 ml. ofacetic anhydride and 6 gm. of anhydrous sodium acetate and the mixtureis heated with stirring over a steam bath for one hour [JACS 77, 4613(1955)]. The light yellow reaction mixture is cooled and the sodiumacetate is filtered off. 750 ml. of other are added to the filtrate andthen petroleum ether (boiling range 30- 60) is added to incipientcrystallization. This is then cooled and filtered. The product,N-(Z-acetamidoethyl) maleimide, is dissolved is isopropanol andrecrystallized from ether-petroleum ether, Ml. Sit-, very hygroscop1c.

ExampleZ By substituting ,G-alanine for the: Z-aminoethylacetamide inthe procedure of Example 1, N-(3-carboxypropyl)maleamic acid and3-maleimidopropionic acid, respectively, are obtained.

By utilizing other substituted alkylamines, e.g., ethoxyethylamine, andsubstituted maleic anhydrides, e.g., Z-methylmaleic anhydride, as thestarting materials in Example 1, other compounds of this invention areobtained.

Example A solution for infusion is prepared by dissolving 30 mg. ofN-(Z-acetamidoethyl)maleimide and 50 mg. of heparin in 1000 ml. of 5%glucose-water.

What is claimed is:

1. A compound of the formula Bi -lower alky1eneN wherein R is a memberof the group consisting of hydrogen and lower alkyl, and R is a memberof the group consisting of lower alkoxy, carboxy and -NH-lower alkanoyl,said lower alkanoyl groups having two to seven carbon atoms.

2. A compound of the formula lower alkanoyl-NH-lower alkyleneN 3.N-(Z-acetamidoethyl)maleimide. 4. 3-maleimidopropionic acid.

References Cited UNITED STATES PATENTS 2,743,260 4/ 6 Tawney 260782,790,787 4/ 1957 Tawney 260-65 3,211,747 10/ 1965 Johnson 260-3263 ALEXMAZEL, Primary Examiner. J. H. NARCAVAGE, Assistant Examiner.

1. A COMPOUND OF THE FORMULA